The present invention relates to a process for the resolution of (R,S)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzene-sulfonamide, also known as tamsulosin, into optically enriched and/or optically pure enantiomers and to compounds and compositions useful therein as starting materials, including solid racemic tamsulosin free base and a process of producing the same, and to products thereof.
The compound 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-benzenesulfonamide of the formula (1) 
is a commercially marketed pharmaceutically active substance useful for the treatment of cardiac insufficiencies and benign prostatic hyperplasia. It is disclosed in EP34432 and U.S. Pat. No. 4,731,478. The molecule, which will be further denoted as xe2x80x9ctamsulosin,xe2x80x9d has one asymmetric carbon (indicated by an asterisk in the above formula (1)), thus allowing for the existence of two enantiomers, conventionally denoted as (R)- or (S)-enantiomers. Both the free base and its acid addition salts may comprise either one or both of the two enantiomers. The single enantiomers have distinctive optical activity in polarized light and they also differ in their pharmaceutical activities. The commercially marketed product is the hydrochloride salt of the (R)-enantiomer of tamsulosin which is levorotary or (R)(xe2x88x92) tamsulosin hydrochloride.
EP34432/U.S. Pat. No. 4,731,478 discloses, inter alia, two general processes that may provide tamsulosin. One general process (hereinafter xe2x80x9cprocess Axe2x80x9d) comprises a reductive amination of a benzylmethylketone compound with a substituted phenoxyethylamine. To make tamsulosin, the corresponding species would be represented by formulae (4) and (5), respectively. 
However, neither these compounds nor the details of an actual production process leading to tamsulosin using this process is set forth. Instead, process A was exemplified only for alkylsulfonamide derivatives. Accordingly, the compounds (4) and (5) were also not prepared as chemical entities. Further, the exemplified products of process A, see examples 4 and 5, were crystallized as the hydrochloride salt of the racemate. If process A is applied for the synthesis of tamsulosin, the result would allow for producing a racemic tamsulosin isolated in the form of a hydrochloride salt and not as the free base.
The second process (hereinafter xe2x80x9cprocess Bxe2x80x9d) generically teaches conversion of a hydroxylated analogue into the desired sulfonamide via a chloro-analogue. For making tamsulosin, the hydroxy analogue would be a compound of formula (8). 
It was disclosed therein that the starting hydroxy-analogues may be prepared according to the methods of GB 2006772, which correspond to DE 2843016 and U.S. Pat. No. 4,217,305. However, none of these documents specifically show the formation of this hydroxy-tamsulosin intermediate compound. Further, it appears in both U.S. Pat. No. 4,731,478 and GB 2006772 that only racemic tamsulosin and racemic hydroxy-tamsulosin, respectively, would be prepared by this general reaction scheme, and not the pure enantiomer. Note that tamsulosin was not prepared by this process in U.S. Pat. No. 4,731,478. It can be derived that condensation of the compound (5) with a suitable reaction partner (geminal halohydrin or oxiran), according to GB 2006772, would produce racemic hydroxy-tamsulosin that would then be correspondingly converted to racemic tamsulosin. Moreover, as in process A, the examples for the related compounds, Examples 1-3, are isolated as HCl salts via crystallization and not as the free base.
While U.S. Pat. No. 4,731,478 does disclose racemic tamsulosin HCl in Example 20, it does not show how the compound was made. Apparently the compound was isolated as the HCl salt and not as the free base.
A method of resolution of racemic tamsulosin into optical isomers was not disclosed in above prior art documents. The only process disclosed in U.S. Pat. No. 4,731,478 that obtains optically pure enantiomeric forms is not in accord with process A or process B, but instead comprises reacting optically pure 5-((2-amino-2-methyl)ethyl)-2-methoxybenzenesulfonamide with 2-(o-ethoxyphenoxy)ethyl bromide to form the corresponding (R)- or (S)-tamsulosin. See Examples 33(a) and 33(b). Known processes for providing the optically pure amine, e.g. processes disclosed in JP 58-18353, EP257787, JP 02-679248, are lengthy and complicated. If the starting amine does not have a desired optical purity, the produced tamsulosin would accordingly be prepared in an optically impure form (in a mixture of enantiomers). No method is known how to purify such an optically impure product.
It would be desirable to have a method to resolve optically impure tamsulosin, including racemic tamsulosin. Specifically, it is desirable to provide a process for the resolution of a racemic tamsulosin or a mixture of tamsulosin enantiomers, which could manufacture the desired enantiomer, particularly the (R) enantiomer, in a desired purity. But to carry out such a resolution method, it would be further desirable to first provide tamsulosin free base, especially racemic tamsulosin free base, in solid state and preferably in a relatively pure form. However, none of these procedures or substances is taught in the above-described prior art.
The present invention relates to the resolution of tamsulosin enantiomers by the use of diastereomeric salts thereof, especially camphor sulfonate salts, by crystallization and to the compounds, compositions, and processes used therein and produced thereby. In particular, one aspect of the invention relates to a process comprising preferentially precipitating one diastereomeric sulfonate salt of tamsulosin from a solution containing a pair of diastereomeric sulfonate salts of tamsulosin to form diastereomeric enriched precipitate and diastereomeric enriched solute. The enriched tamsulosin free base enantiomer can be liberated from either the enriched precipitate or the enriched solute. The precipitation can be repeated with or without first liberating the free base.
Similarly, another aspect of the present invention relates to a method of separation of enantiomers of tamsulosin by fractional crystallization comprising using a chiral camphor sulfonic acid in said crystallization.
A further aspect of the invention relates to a compound selected from the group consisting of (R)-tamsulosin-(+)-camphor-10-sulfonate, (S)-tamsulosin-(+)-camphor-10-sulfonate, (R)-tamsulosin-(xe2x88x92)-camphor-10-sulfonate, and (S)-tamsulosin-(xe2x88x92)-camphor-10-sulfonate. For clarity, while these salts are diastereomers, the (R) and (S) denotation indicates the stereo configuration of the tamsulosin moiety and (+) and (xe2x88x92) denotation indicates the optical activity of the acid from which the diastereomeric salt was formed. These diastereomers are particularly useful in preferential precipitation according to the present invention.
Another aspect of the present invention relates to a composition comprising (R) and (S) tamsulosin or the salts thereof, wherein one of said (R) or (S) forms exceeds the amount of the other within the range of 60:40 to 95:5, preferably 65:35 to 95:5 parts by weight. Such compositions can be formed by the process of the present invention and/or are useful as substrates in the resolution process of the present invention.
A further aspect of the invention relates to racemic tamsulosin free base in a solid state. The free base is a useful starting material for the resolution process of the present invention. Typically the free base is a precipitate and is preferably in crystalline form. Crystalline tamsulsoin free base of the present invention exhibits polymorphism and two particular polymorphic forms, hereinafter identified as Form 1 and Form 2, represent preferred aspects of the present invention.
Obtaining tamsulosin free base in solid state is another aspect of the present invention. For example, the present invention includes a process for producing racemic tamsulosin free base in solid state, which comprises precipitating racemic tamsulosin free base from a solution containing racemic tamsulosin in a solvent, wherein the solvent comprises at least one of water or a lower alcohol. Preferred solvents include water, methanol, water/methanol mixtures and ethyl acetate/methanol mixtures. The tamsulosin solution can be formed by dissolving a tamsulosin residue into the solvent or by treating a tamsulosin acid addition salt with a base.
Isolation of tamsulosin free base in solid state is not limited to the racemate, however, and another aspect of the present invention relates to a process for isolation of tamsulosin free base, which comprises treating an acid addition salt of tamsulosin in a solvent with a base and precipitating tamsulosin free base from the solvent, wherein the solvent comprises water, a lower alcohol or both. The tamsulosin free base can be racemic or not. The acid addition salt is normally the hydrochloride salt but is not limited thereto and includes, for example, the camphor-10-sulfonic acid salt thereof.
An additional aspect of the present invention relates to a sulfonic acid salt of 2-(o-ethoxyphenoxy)ethylamine, especially the methane sulfonate or tosylate salts thereof, as well as to (3-aminosulfonyl-4-methoxy)phenylacetone. These compounds are novel intermediates that are useful in the production of tamsulosin free base.